Halogenated steroids

Abstract

Novel halogenated steroids of the formula ##STR1## in which X represents a halogen atom having a maximum atomic number of 17, Y represents a hydrogen atom or hydroxyl, and R represents an alkyl radical having a maximum of 6 carbon atoms, and their 1,2-dehydro derivatives and the processes for the production thereof.

What is claimed is: 
     
       1. A halogenated steroid of the formula ##STR4## in which X represents a halogen atom having a maximum atomic number of 17, Y represents a hydrogen atom or hydroxyl, and   R represents an alkyl radical having a maximum of 6 carbon atoms and the dotted line in the 1,2-position represents the additional double bond of a 1,2-dehydro derivative.     
     
     
       2. A compound of the formula A according to claim 1 in which Y represents hydroxyl. 
     
     
       3. A compound of the formula A according to claim 1 in which Y represents hydrogen. 
     
     
       4. A compound of the formula A according to claim 1 in which X represents chlorine. 
     
     
       5. A compound of the formula A according to claim 1 in which R represents ethyl. 
     
     
       6. A compound of the formula A according to claim 1 that is saturated in the 1,2-position. 
     
     
       7. 21-chloro-6.alpha.-fluoro-11β,17α-dihydroxy-16β-methyl-pregn-4-ene-3,20-dione 17-propionate. 
     
     
       8. 21-chloro-6.alpha.-fluoro-17α-hydroxy-16β-methyl-pregn-4-ene-3,20-dione 17-propionate. 
     
     
       9. 21-chloro-6.alpha.-fluoro-11β,17α-dihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione 17-propionate. 
     
     
       10. 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione 17-propionate. 
     
     
       11. A pharmaceutical preparation containing one of the compounds defined in claim 1 together with a pharmaceutical carrier. 
     
     
       12. A pharmaceutical preparation containing one of the compounds defined in one of claims 7 to 10 together with a pharmaceutical carrier. 
     
     
       13. Therapeutic method of alleviating or eliminating pathological inflammatory conditions in a warm-blooded animal, characterised by the administration to this warm-blooded animal of a compound according to claim 1 alone or in the form of a pharmaceutical preparation in quantities that are effective in the alleviation or elimination of the inflammation in this warm-blooded animal. 
     
     
       14. Method according to claim 13 in which an inflammation of the skin or mucosa is treated by the topical administration of the active substance. 
     
     
       15. Method according to claim 13 or 14 in which the warm-blooded animal treated is a human being. 
     
     
       16. Process for the manufacture of halogenated steroids of the formula ##STR5## in which X represents a halogen atom having a maximum atomic number of 17, Y represents a hydrogen atom or hydroxyl, and   R represents an alkyl radical having a maximum of 6 carbon atoms, the dotted line in the 1,2-position representing the additional double bond of a 1,2-dehydro derivative, wherein:     (a) 21-(fluoro or chloro)-3β-hydroxy-16-methyl-pregna-5,16-dien-20-one 3-lower alkanoyl ester is treated with a peracid and to form the corresponding 5,6-epimers, which are separated from each other in a resulting mixture of 5,6;16α,17-diepoxides, is treated with hydrogen fluoride, or any obtained 5β,6;16α,17-diepoxide is reacted with a strong oxygen-containing acid, to form the resulting 5α,6β,17α-trihydroxy-16-methylene compound which is then treated with an organic sulphonyl halide in the presence of 2,4,6-collidine or 2,6-lutidine, to form the resulting 5α,6-epoxy-17-α-hydroxy-16-methylene compound, which is then reacted with hydrogen fluoride, to form the corresponding 21-(fluoro or chloro) 6β-fluoro-5α,17α-dihydroxy-3β-lower alkanoyloxy-16-methylene-pregnan-20-one,   (c) the resulting 21-(fluoro or chloro)-6β-fluoro-5α,17α-dihydroxy-3βlower alkanoyloxy-16-methylene-pregnan-20-one, the two free hydroxyl groups are esterified by a lower alkanecarboxylic acid,   (d) the resulting 21-(fluoro or chloro)-6β-fluoro-3β,5α,17α-trihydroxy-16-methylene-pregnan-20-one 3-lower alkanoyl-5,17-di-lower alkanecarbonyl ester is catalytically hydrogenated,   (e) the resulting 21-(fluoro or chloro)-6β-fluoro-3β,5α,-17α-trihydroxy-16β-methyl-pregnan-20-one 3-lower alkanoyl-5,17-di-lower alkanecarbonyl ester, the esterified 3-hydroxyl group is freed by selective hydrolysis and subsequently oxidised into the 3-oxo group,   (f) the resulting 21-(fluoro or chloro)-6β-fluoro-5α,17α-di-lower alkanecarbonyloxy-16β-methyl-pregnane-3,20-dione is treated with an acid in order to remove the 5-positioned lower alkanecarbonyloxy group and, with or without converting any resulting compound having 6β-fluoro, by catalytic treatment with a strong acid, into the 6α-fluoro isomer, and, where Y represents hydroxyl, the resulting end product of the formula A in which Y represents hydrogen is hydroxylated in the 11β-position by means of the enzymatic system of a 11β-hydroxylating micro-organism, and where the compound of formula A is a 1,2-dehydro compound the resulting 1,2-saturated end product of the formula A is dehydrogenated.   
     
     
       17. Process according to claim 16, wherein the starting material of step (a) is 21-(fluoro or chloro)-3β-hydroxy-16β-methyl-pregna-5,16-dien-20-one 3-formate, obtained by reacting 3β-hydroxy-16-methylpregna-5,16-dien-20-one or a carboxylic acid ester thereof with a lower alkyl oxalate or formate in the presence of an alkali metal lower alcoholate, converting the resulting 21-(lower alkoxalyl or formyl)-5,16-dien-20-one derivative into 21-diazo-3β-hydroxy-16-methylpregna-5,16-dien-20-one by reacting with an organic sulphonylazide, treating the diazo-derivative with hydrogen fluoride or hydrogen chloride, and esterifying the resulting 21-(fluoro or chloro)-3β-hydroxy-16-methyl-pregna-5,16-dien-20-one with 85% aqueous formic acid. 
     
     
       18. Process according to claim 16, wherein the starting material of step (a) is 21-(fluoro or chloro)-3β-hydroxy-16β-methyl-pregna-5,16-dien-20-one 3-acetate, obtained by reacting 3β-hydroxy-16-methylpregna-5,16-dien-20-one or a 3-carboxylic acid ester thereof with a lower alkyl oxalate or formate in the presence of an alkali metal lower alcoholate, converting the resulting 21-(lower alkoxalyl or formyl)-5,16-dien-20-one derivative into 21-diazo-3β-hydroxy-16-methylpregna-5,16-dien-20-one by reacting with an organic sulphonylazide, treating the diazo-derivative with hydrogen fluoride or hydrogen chloride, and esterifying the resulting 21-(fluoro or chloro)-3β-hydroxy-16-methyl-pregna-5,16-dien-20-one with acetic anhydride in 2,4,6-collidine or 2,6 -lutidine. 
     
     
       19. Process according to claim 16, wherein in carrying out process stage (e), the 21-(chloro or fluoro)-6β-fluoro-3β,5α,17α-trihydroxy-16β-methylpregnan-20-one 3-formate-5,17-di-lower alkanecarbonyl ester is hydrolysed with an alkali metal hydrogen carbonate at room temperature. 
     
     
       20. Process according to claim 16, wherein, in carrying out process stage (e), a 21-(chloro or fluoro)-6β-fluoro-3β,5α,17α-trihydroxy-16β-methylpregnan-20-one 3-lower alkanoyl-5,17-di-lower alkanecarbonyl ester is hydrolyzed with a strong acid in one or more alkanols. 
     
     
       21. Process according to claim 18, wherein in carrying out process stage (e), a 21-(chloro or fluoro)-6β-fluoro-3β-5α,17α-trihydroxy-16β-methylpregnan-20-one 5,17-di-lower alkanecarbonyl ester is oxidized with a compound of hexavalent chromium. 
     
     
       22. Process according to claim 16, wherein in stage (c), the two free hydroxyl groups in the 21-(fluoro or chloro)-6β-fluoro-5α,17α-dihydroxy-3β-lower alkanoyloxy-16-methylene-pregnan-20-one are esterified by treatment with a mixed anhydride of a lower alkanecarboxylic acid with trifluoroacetic acid. 
     
     
       23. Process according to claim 16, wherein platinum is used as the hydrogenation catalyst in stage (d). 
     
     
       24. Process according to claim 16, wherein in process stage (e), a 21-(fluoro or chloro)-6β-fluoro-3β,5α,17α-trihydroxy-16β-methyl-pregnan-20-one 5,17-di-lower alkanecarbonyl ester ioxidized with a solution of chromium trioxide in aqueous sulphuric acid, in acetone. 
     
     
       25. Process according to claim 16, wherein in order to carry out both steps of the process stage (f) simultaneously, a 21-(fluoro or chloro)-6β-fluoro-5α,17α-di-lower alkanecarbonyloxy-16β-methyl-pregn-a-one-3,20-dione is treated with anhydrous hydrogen chloride or hydrogen bromide in a halogenated hydrocarbon. 
     
     
       26. Process according to claim 16, wherein the biological 11β-hydroxylation is carried out with the 11β-hydroxylating enzyme system of Curvularia lunata in a growing or static culture. 
     
     
       27. Process according to claim 16, wherein dehydrogenation is effected with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. 
     
     
       28. Process according to claim 16, wherein, carrying out, additionally, the optional step of the microbial 11β-hydroxylation, a compound of the formula A is manufactured in which Y represents hydroxyl. 
     
     
       29. Process according to claim 16, wherein a compound of the formula A is manufactured in which Y represents hydrogen. 
     
     
       30. Process according to claim 16, wherein, employing 3β-lower alkanoyloxy-21-chloro-16-methylpregna-5,16-dien-20-one as starting material, a compound of the formula A is manufactured in which X represents chlorine. 
     
     
       31. Process according to claim 16, wherein, esterifying with a derivative of propionic acid on stage (c) a compound of the formula A is manufactured in which R represents ethyl. 
     
     
       32. Process according to claim 16, wherein a compound of the formula A is manufactured that is saturated in the 1,2-position. 
     
     
       33. Process according to claim 16, wherein employing 3β-lower alkanoyloxy-21-chloro-16-methylpregna-5,16-dien-2-one as starting material, esterifying with a derivative of propionic acid in state (c) and carrying out, additionally, the optional step of the microbial 11β-hydroxylation, 21-chloro-6α-fluoro-11β,17α-dihydroxy-16β-methyl-pregn-4-ene-3,20-dione 17-propionate is manufactured. 
     
     
       34. Process according to claim 16, wherein, employing 3β-lower alkanoyloxy-21-chloro-16-methylpregna-5,16-dien-20-one as starting material and esterifying with a derivative of propionic acid in stage (c), 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregn-4-ene-3,20-dione 17-propionate is manufactured. 
     
     
       35. Process according to claim 16, wherein, employing 3β-lower alkanoyloxy-21-chloro-16-methylpregna-5,16-dien-20-one as starting material, esterifying with a derivative of propionic acid in stage (c), and in any sequence carrying out, additionally, the optional step of the microbial 11β-hydroxylation and 21-chloro-6α-fluoro-11β,17α-dihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione 17-propionate is manufactured. 
     
     
       36. Process according to claim 16, wherein employing 3β-lower alkanoyloxy-21-chloro-16-methylpregna-5,16-dien-2-one as starting material, esterifying with a derivative of propionic acid in stage (c), and carrying out the additional optional step of 1,2-dehydrogenation, 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione 17-propionate is manufactured.